Diabetes is a huge problem in the US and has more than doubled world-wide since 1980 to over 345 million people. Self-monitoring of blood glucose is recommended for diabetic patients as the current standard of care. There is a need by people with Diabetes to monitor glucose noninvasively and avoid the frequent (up to 5 times daily) finger or forearm pricks required today. There is an unmet need for simple, non-invasive self-glucose monitoring devices for people with both Type 1 insulin dependent diabetes and especially for the majority of patients who require less intensive treatment strategies such as those with controlled type 2 diabetes due to life-style modification, oral agent therapy or simple combination oral agent/basal insulin therapy. An equal number of individuals with impaired glucose tolerance and pre-diabetes would benefit from a non-invasive monitoring method to assess their own glucose several times weekly or monthly to detect disease progression. There are also a significant number of patients for whom there is a need for simple non-invasive monitoring for a determinate period of time including women with gestational diabetes, who may or may not be taking insulin, patients with insulin resistance due to heart failure and individuals undergoing chemotherapy or transplant anti-rejection therapies. Thus, there is a very large unmet need for simple non-invasive system.
Existing invasive glucose sensors are commonly used to measure the blood-glucose level of individuals with diabetes. Just by way of example, such sensing systems may be utilized by drawing blood and directly sensing the concentration of glucose in the blood. The problem with these types of sensors is that they are painfully invasive, time consuming, raises concerns about blood borne pathogens, can be embarrassing, and especially troublesome for children. Continuous glucose monitoring (CGM) systems are also available but they are indwelling, suffer from many of the same issues as finger stick devices, and additionally require frequent calibration.
An improved alternative to these invasive glucose sensors is an optical glucose sensor, which is noninvasive. Optical glucose sensors are capable of quantitatively determining the concentration of optically active substances in the human body. As understood by those skilled in the art, the plane of polarization of linearly polarized light rotates as it interacts with optically active material, such as glucose.
FIG. 1 illustrates the principle by which the concentration of an optically active material can be measured utilizing an optical sensor. Unpolarized monochromatic light 100 is passed through a vertical polarizer 105. The linearly polarized light 110 exiting the vertical polarizer 105 is subsequently passed through an optically active sample 115, such as a sample containing glucose. The optically active sample rotates the plane of polarization of the linearly polarized light 110 by an angle, ϕ, which is proportional to the concentration of the optically active sample. The light exiting the optically active sample is passed through a horizontal polarizer 120. The intensity of the light passing through the horizontal polarizer 120 and detected by the light detector 125 is related to the horizontal component of the plane of polarization introduced by the rotation of the vertically polarized light by the optically active sample 115. Therefore, for a fixed path length through the sample chamber the intensity of the light measured by the detector 125 is proportional to the concentration of the optically active sample.
The fluid contained in the anterior chamber of the eye is known as the aqueous humor and is relatively scatter free, making the anterior chamber an ideal sampling point to detect glucose concentrations utilizing an optical sensor. The diffusion or secretion of glucose into the aqueous humor is highly correlated to the amount of glucose found in the blood. More specifically, the aqueous humor fluid yields a glucose content equal to approximately 70% of that found in blood. Thus, an individual's blood glucose concentration can be ascertained by an optical glucose sensor that detects changes in the plane of polarization of linearly polarized light directed through the anterior chamber of the individual's eye. Examples of such optical glucose sensors may be found in U.S. Pat. Nos. 6,885,882 and 5,209,231, which are herein incorporated by reference.
Although the example process illustrated in FIG. 1 is suitable for measuring large concentrations of optically active substances, additional measures must be taken to accurately measure the relatively small physiological concentration of glucose in the aqueous humor. As illustrated in FIG. 2, a polarization modulation device 225 is added to the example system of FIG. 1 to modulate the plane of polarization of linearly polarized light using the Faraday Effect. According to the Faraday Effect, the plane of polarization of light traveling through a magneto-optic material is rotated by an angle proportional to the magnitude of a magnetic field parallel to the propagation direction of the light, the Verdet constant of the magneto-optic material, and the length of the material according to the formula β=vBL, where β is the magnitude of rotation of the plane of polarization, B is the applied magnetic field, v is the Verdet constant of the magneto-optic material, and L is the length of the magneto-optic material.
The induced modulation allows for the detection of the submillidegree rotational changes, in the plane of polarization, in the presence of optically active substances (e.g., glucose) in the aqueous humor. Due to the relatively short path length and small analyte concentrations present in the aqueous humor, detection of changes in the plane of polarization on the order of 0.4 millidegrees are needed to obtain a system sensitivity comparable to current glucose sensing devices. Utilizing the modulation device, the concentration of glucose can be determined based on the difference between the observed intensity of light at light detector 125 and the expected intensity based on the intentionally induced modulation. Therefore, modulation makes it possible to isolate and detect the small variations in the rotation of the plane of polarization caused by the changes in the concentration of glucose present in the aqueous humor. Detection of the small rotational changes in the optical signal due to the presence of glucose is possible through the use of lock-in amplifiers used to detect the modulated signal. This greatly increases the signal to noise ratio through isolating the modulated signal, thereby, reducing the effects of lower frequency sources of noise such as 60 Hz frequencies emitted by light fixtures in the area of the sampling, thereby improving the sensitivity of the system enabling glucose detection by means of coupling polarized light across the anterior chamber of the eye.
Thus, according to the system for optically sensing glucose levels illustrated in FIG. 2, a laser 205 emits light 100 into a vertical polarizer 105. The polarized light 110 then passes through a polarization modulation device 225. The polarization modulation device 225 rotates the plane of polarization at a frequency (f) with a modulation depth of ±β by applying a magnetic field parallel to the direction of propagation of the polarized light 110 through a magneto-optic material. The modulated light 230 then passes through the aqueous humor fluid 235 contained in the anterior chamber of the eye 240, wherein the plane of polarization is further rotated according to the concentration of optically active molecules in the aqueous humor fluid 235, wherein glucose is the primary optically active molecule. The modulated light 230 next passes through a horizontal polarizer 120 in the same manner as described above with respect to FIG. 1. A light detector 125 measures the intensity of the modulated light 230 and converts it into an electrical signal to be analyzed by a processing unit 255, such as a personal computer, in order to determine the concentration of glucose in the aqueous humor.